Abstract Alcohol use disorder (AUD) with comorbid major depression (MD) is among the most frequent and serious conditions encountered in clinical practice, for which effective treatment interventions are currently limited. Activation of pro-inflammatory cytokines and pathways are emerging as key pathophysiological factors in the etiology of both alcoholism and major depression. Although immune and inflammatory mechanisms have been studied to a considerable extent in alcoholism and major depression separately, patients with co-occurring alcoholism and major depression are most likely to exhibit substantial inflammation. Pro-inflammatory mechanisms appear to play a bidirectional role in both depression and alcoholism and may underlie the limited treatment response reported in clinical trials. The lack of previously effective treatments demands new intervention modalities and different treatment targets targeting mechanisms underlying such comorbidity. We hypothesize that increased inflammation in these patients represents a major factor fostering decreased treatment response. Thus, patients with comorbid AUD and MD represent an ideal group to test the effect of a potent anti-inflammatory intervention. We propose to use allogeneic human mesenchymal stem cell (ahMSC) therapy, a highly novel treatment pioneered at the University of Miami Miller School of Medicine, to treat a variety of inflammatory conditions. This treatment has been shown to be safe and well-tolerated in a variety of medical disorders and exerts a robust and sustained anti-inflammatory effect. We plan to test the effects of ahMSCs on inflammation and on alcohol and depression outcomes in patients with comorbid AUD and recurrent MD (AUD- MD) preselected for the presence of high inflammatory markers (hsCRP>3 mg/L). Our study has the following Specific Aims: Aim 1. To examine the effects of a single ahMSC infusion on inflammation, as assessed by C- Reactive Protein (CRP) concentrations in a 12-week randomized, placebo-controlled trial in 80 MD-AUD patients (40 active infusion, 40 placebo) all preselected for the presence of inflammation. Aim 2. To examine the effects of the reduction in CRP and other inflammatory markers associated with ahMSC therapy on clinician- administered measures of the severity of alcohol use (TLFB-% heavy drinking days) and depression (MADRS) and global clinical functioning (CGI). Aim 3. To examine the direct (reduction in CRP and other inflammatory biomarkers) and indirect (reduction in alcohol use and depression) effects of ahMSC therapy on secondary study outcomes including, craving, cognition, everyday functioning and perceived quality of life. Aim 4. Our exploratory aim includes assessment of the mediating role of childhood trauma and assessment of the persistence of treatment effects over the one year follow-up period, with collection of blood samples to explore the role of inflammation related-polymorphisms and epigenetics in treatment response. If successful, this treatment would represent a paradigm shift in treating AUD-MD comorbidity and will have a significant impact on the field of therapeutics for other complex conditions in which altered inflammatory mechanisms play a substantial role in their pathogenesis.